Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen.

Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.

Pretransplant immunosuppression followed by reduced-toxicity conditioning and stem cell transplantation in high-risk thalassemia: a safe approach to disease control.

Patients with class 3 thalassemia with high-risk features for adverse events after high-dose chemotherapy with hematopoietic stem cell transplantation (HSCT) are difficult to treat, tending to either suffer serious toxicity or fail to establish stable graft function. We performed HSCT in 18 such patients age ≥7 years and hepatomegaly using a novel approach with pretransplant immunosuppression followed by a myeloablative reduced-toxicity conditioning regimen (fludarabine and i.v. busulfan [Flu-IV Bu]) and then HSCT. The median patient age was 14 years (range, 10 to 18 years). Before the Flu-IV Bu + antithymocyte globulin conditioning regimen, all patients received 1 to 2 cycles of pretransplant immunosuppression with fludarabine and dexamethasone. Thirteen patients received a related donor graft, and 5 received an unrelated donor graft. An initial prompt engraftment of donor cells with full donor chimerism was observed in all 18 patients, but 2 patients developed secondary mixed chimerism that necessitated withdrawal of immunosuppression to achieve full donor chimerism. Two patients (11%) had acute grade III-IV graft-versus-host disease, and 5 patients had limited chronic graft-versus-host disease. The only treatment-related mortality was from infection, and with a median follow-up of 42 months (range, 4 to 75), the 5-year overall survival and thalassemia-free survival were 89%. We conclude that this novel sequential immunoablative pretransplantation conditioning program is safe and effective for patients with high-risk class 3 thalassemia exhibiting additional comorbidities.

Cost utility analysis of reduced intensity hematopoietic stem cell transplantation in adolescence and young adult with severe thalassemia compared to hypertransfusion and iron chelation program.

BACKGROUND: Hematopoieticic stem cell transplantation is the only therapeutic option that can cure thalassemia disease. Reduced intensity hematopoietic stem cell transplantation (RI-HSCT) has demonstrated a high cure rate with minimal complications compared to other options. Because RI-HSCT is very costly, economic justification for its value is needed. This study aimed to estimate the cost-utility of RI-HSCT compared with blood transfusions combined with iron chelating therapy (BT-ICT) for adolescent and young adult with severe thalassemia in Thailand. METHODS: A Markov model was used to estimate the relevant costs and health outcomes over the patients' lifetimes using a societal perspective. All future costs and outcomes were discounted at a rate of 3% per annum. The efficacy of RI-HSCT was based a clinical trial including a total of 18 thalassemia patients. Utility values were derived directly from all patients using EQ-5D and SF-6D. Primary outcomes of interest were lifetime costs, quality adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in US ($) per QALY gained. One-way and probabilistic sensitivity analyses (PSA) were conducted to investigate the effect of parameter uncertainty. RESULTS: In base case analysis, the RI-HSCT group had a better clinical outcomes and higher lifetime costs. The incremental cost per QALY gained was US $3,236 per QALY. The acceptability curve showed that the probability of RI-HSCT being cost-effective was 71% at the willingness to pay of 1 time of Thai Gross domestic product per capita (GDP per capita), approximately US $4,210 per QALY gained. The most sensitive parameter was utility of severe thalassemia patients without cardiac complication patients. CONCLUSION: At a societal willingness to pay of 1 GDP per capita, RI-HSCT was a cost-effective treatment for adolescent and young adult with severe thalassemia in Thailand compared to BT-ICT.

Allogeneic hematopoietic stem cell transplantation for children with severe aplastic anemia.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment for severe aplastic anemia (SAA). This is a single institutional review to study the feasibility of using allo-SCT for Thai children with SAA. MATERIAL AND METHOD: Nine children with SAA (7 matched-sibling donor-SCT, 1 matched-unrelated donor-SCT and 1 haploidentical-SCT) underwent allo-SCT between October 2002 and September 2010. Cyclophosphamide and anti-thymocyte globulin (CY/ATG) were used as conditioning regimen for 4 patients with matched-sibling donor-SCT CY/ATG and fludarabine were used for 3 patients with matched-sibling donor-SCT and one patient with haplo-identical SCT. One matched-unrelated donor-SCT received CY/ATG and total body irradiation. RESULTS: Eight of 9 patients (89%) achieved neutrophil engraftment within 13.5 days (range 6.0-22.0). One matched-sibling donor-SCT recipient who failed to achieve engraftment died from acute renal failure and gram-negative sepsis on day 21 post allo-SCT. One matched-sibling donor-SCT case developed late graft failure on day 72 and died from invasive fungal infection. For graft versus host disease (GVHD), a haplo-identical-SCT patient died from steroid refractory grade IV acute GVHD. At last follow-up, six patients (67%) alive at a median follow-up time of 76.4 months (range 2.3-88.8). Overall survival (OS) and event-free survival (EFS) at 5 year was 63% and 65%, respectively. CONCLUSION: Allo-SCT is a feasible curative treatment for children with SAA in Thailand. Graft failure and severe GVHD in alternative donors SCT are responsible for major causes of death. OS and EFS probabilities are stable after the first year post transplant.

The second mini-transplant for unstable mixed chimerism within the first 100 days after hematopoietic stem cell transplant in severe thalassemia.

Allogeneic HSCT is the only curative treatment for severe thalassemia disease. MC occurs in one-third of these patients within the first two months after HSCT; this is a major risk factor of graft rejection, especially when RHCs are more than 25%. There is still no consensus for the management of MC, especially in the early phase of HSCT. The DLI has also been described in the treatment of MC following HSCT for hemoglobinopathies, but its success is still not guaranteed. The second HSCT has been an approach used in an attempt to cure patients who reject their graft. Concern about toxicity of conditioning regimen, the second HSCT is usually delayed for at least a year after the first HSCT. We would like to demonstrate the successful use of the second mini-allogeneic HSCT in hemoglobin E/ß-thalassemia with evidence of unstable MC in the first 100 days after allogeneic HSCT to prevent further graft loss after allogeneic HSCT.

Normalized coagulation markers and anticoagulation proteins in children with severe ß-thalassemia disease after stem cell transplantation.

The hypercoagulable state is well recognized in patients with severe ß-thalassemia disease. One of the mechanisms of chronic hypercoagulable state is the abnormal expression of phosphatidylserine on red blood cells (RBC). This study aimed to determine the coagulable state in patients with severe ß-thalassemia disease following successful stem cell transplantation (SCT). Subjects were classified into three groups: normal controls (NC), ß-thalassemia disease receiving regular transfusion (Thal-RT) and ß-thalassemia disease post SCT (Thal-SCT). Sixty eight subjects, aged 3-17years, consisting of 21 NC, 28 Thal-RT and 19 Thal-SCT were enrolled. After SCT, the annexin V level in Thal-SCT was normalized. At the median follow-up time of 70.3 (50.9-84.2) months after SCT, the levels of coagulation markers (thrombin antithrombin complex, prothrombin fragment and D-dimer) and anticoagulation proteins (protein C, S and antithrombin activities) returned to the levels similar to controls.

Ex vivo generation of cytokine-induced killer cells (CD3+ CD56+) from post-stem cell transplant pediatric patients against autologous-Epstein-Barr virus-transformed lymphoblastoid cell lines.

EBV-PTLDs affect as high as 20% of SCT recipients especially those with T-cell depleted grafts while high mortality rates were also noted. Adoptive allogeneic and autologous CTLs have a therapeutic potential in this setting. However, the process of expansion of these cells is tedious and time consuming in both allogeneic and autologous CTL generation. For the allogeneic SCT, another major obstacle is unavailability of donors especially in an unrelated SCT setting. The aim of the present study was therefore to investigate the efficacy of autologous CIK cells (CD3+ CD56+) against autologous EBV-LCLs from post-SCT pediatric patients. We could demonstrate that CIK cells can be generated within two wk and did show the significant cytotoxicity against autologous EBV-LCLs. CIK cells may provide a potent tool for use in post-transplantation adoptive immunotherapy.